Multiple Endocrine Neoplasia Type 2 (MEN2) is an autosomal dominant condition caused by heterozygous activating mutations in the RET gene. Information in this protocol is limited to heterozygous activating RET mutations known to be associated with a clinical phenotype of MEN2. Some cases of Hirschsprung disease are caused by germline loss-of-function mutations in the RET gene and this situation is not covered by this protocol.

There are 2 clinical subtypes of MEN2:

MEN2A: predisposition to medullary thyroid carcinoma (MTC), adrenal phaeochromocytoma and primary hyperparathyroidism due to parathyroid adenoma/hyperplasia. Some patients have other signs such as cutaneous lichen amyloidosis

Familial medullary thyroid cancer (FMTC) is a phenotypic variant of MEN2A with decreased penetrance for adrenal phaeochromocytoma and primary hyperparathyroidism rather than a distinct entityr.

This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour. The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up.

Individuals with a germline mutation in the RET gene (all MEN2 subtypes)

Exclusion criteria

Individuals at 50% risk (they should be encouraged to have mutation testing to determine their mutation status given the requirement for surgery)

Individuals with apparently sporadic medullary thyroid cancer and no other features of MEN2 and RET genetic testing has not identified a mutation

Individuals or their relatives where there is a clinical diagnosis of an apparently sporadic case of MEN2A or MEN2B and RET genetic testing has not identified a mutation

Individuals who have medullary thyroid cancer and a family history of medullary thyroid cancer but no personal or family history of other features of MEN2 (familial MTC)where sequencing of the entire RET coding region has not identified a mutation. After the initial evaluation offer repeated screening at 1-3 year intervalsr

Rare families who meet the clinical criteria for familial MEN2A or 2B where sequencing of the entire RET coding region has not identified a mutation. After the initial evaluation offer repeated screening at 1-3 year intervalsr

The location of the mutation in the RET gene has a strong association with the age of onset, penetrance and aggressiveness of MTC. The American Thyroid Association's (ATA) original classification system placed RET mutations into one of 4 "letter categories" (A to D) based on MTC risk. The most recent guidelines use a different classification which clearly states the MTC risk: most category A and B mutations are moderate risk, most category C high risk (includes codon 634 mutations) and category D highest risk (either MEN2B phenotype or M918T); see table belowr

# Surgery should only be delayed beyond 10-15 years of age in the presence of all of the following features; 1. normal annual basal and/or stimulated calcitonin; 2. normal annual neck ultrasound ; 3. less aggressive family history of medullary thyroid cancer; 4. parents accept the small risk of the child developing MTC that is not cured by thyroidectomy (i.e. informed parental decision against surgery); 5. regular follow up with endocrinologistr

*In this document free metanephrines refers to the separate measurement and reporting of the unconjugated (free) metabolites metanephrine and normetanephrine, and total refers to the sum of the free and conjugated metabolite.**Clinically significant parathyroid disease is absent in MEN2B.

Medullary thyroid cancer

Surgical

In MEN2, early intervention with prophylactic thyroidectomy has been shown to significantly alter the mortality associated with MTC. The most recent guidelines suggest a watchful waiting approach may be reasonable in some patients with an ATA moderate risk mutation where the risk of medullary thyroid cancer in childhood and adolescence is lower. However, regardless of mutation category most RET mutation carriers will eventually need thyroidectomy. There are risks in delaying surgery in family members who have inherited a mutated RET allele; regardless of the patient's age, the decision to delay risk reducing surgery must balance the risks of thyroidectomy against the possibility that MTC develops and it is not cured by therapeutic thyroidectomy.r

Surveillance

The most recently published expert consensusr recommends that after surgery consideration be given to screening with annual calcitonin, although this recommendation is made in the absence of high level evidence.

Adrenal phaeochromocytoma

Surveillance

There is evidence to support the routine use of catecholamine screening in patients at high risk of phaeochromocytoma.rr
Urine and plasma free plasma metanephrines have diagnostic sensitivities greater than 97% with better specificity (85-100%) than total metanephrines or catecholamines.r Measurement of parent catecholamines (noradrenaline, adrenaline and dopamine) has low diagnostic sensitivity (<85%) and is not recommended.

The most recently published expert consensusr recommends biochemical screening only, with radiological imaging reserved for the workup of individuals with abnormal results. There is no consensus on the role of imaging to screen for adrenal phaeochromocytoma in individuals with no symptoms and normal biochemistry.

The age to commence screening for adrenal phaeochromocytoma and the optimal screening interval are both unclear. The most recently published expert consensusr recommends screening for adrenal phaeochromocytoma occur annually and start by age 11 years in children with the highest risk mutations (ATA high and highest risk), and by age 16 years for lower risk mutations (ATA moderate risk).

There is some evidence that screening should occur more frequently in early-mid adulthood (20-50 years; when the risk of tumours is highest) compared to childhood and later adulthood.r

Parathyroid disease

Surveillance

Primary hyperparathyroidism is most strongly associated with codon 630 and 634 mutations and is less commonly described in other RET mutations (Waguespack et al 2011). Clinically significant primary hyperparathyroidism is rare in childhood.

The age to commence screening for primary hyperparathyroidism and the optimal screening interval are both unclear. The most recently published expert consensusr recommends screening for primary hyperparathyroidism occur annually and start by age 11 years in children with ATA high risk mutations, and by age 16 years for ATA moderate risk mutations.

Primary hyperparathyroidism is not associated with MEN2B and screening is not recommended in individuals with this phenotype.

PGD / prenatal diagnosis

With early recognition MEN2 is a treatable disorder. All RET mutation carriers of childbearing age, particularly those with MEN2B, should be made aware of the option of pre-implantation or prenatal diagnostic testing.

First degree (blood) relatives (parents/brothers/sisters/children) are at 50% risk of having inherited the gene mutation or having the condition. First degree relatives should be referred to a local family cancer clinic.

Medullary thyroid carcinoma (MTC) and the multiple endocrine neoplasia (MEN) type 2 syndromes are rare but important endocrine diseases that are increasingly managed by pediatric providers. MTC is generally associated with a favorable prognosis when diagnosed during childhood, where it frequently occurs secondary to activating mutations in the RET proto-oncogene and arises from pre-existing C-cell hyperplasia. MEN2A accounts for 90-95% of childhood MTC cases and is most commonly due to mutations in codon 634 of RET. MEN2B is associated with the most aggressive clinical presentation of MTC and is almost always due to the Met918Thr mutation of RET. Surgery is the primary treatment and only chance of cure, although the advent of targeted therapies seems to be improving progression-free survival in advanced cases. Since the discovery of the role of RET in MEN2A, considerable advances in the management of this syndrome have occurred, and most of the children with MEN2A who have undergone early thyroidectomy will now lead full, productive lives. Strong genotype-phenotype correlations have facilitated the development of guidelines for interventions. Contemporary approaches for deciding the appropriate age at which surgery should take place incorporate data from ultrasonography and calcitonin measurements in addition to the results of genotyping. To optimize care and to facilitate ongoing research, children with MTC and the MEN2 syndromes are optimally treated at tertiary centers with multidisciplinary expertise

Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical-risk profiles. Presentation, age-dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609-- >620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected

RET testing in multiple endocrine neoplasia type 2 for molecular diagnosis is the paradigm for the practice of clinical cancer genetics. However, precise data for distinct mutation-based risk profiles are not available. Here, we survey the clinical profile for one specific genotype as a model, TGC to TGG in codon 634 (C634W). By international efforts, we ascertained all available carriers of the RET C634W mutation. Age at diagnosis, penetrance, and clinical complications were analyzed for medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism (HPT), as well as overall survival. Our series comprises 92 carriers from 20 unrelated families worldwide. Sixty-eight subjects had MTC diagnosed at age 3-72 years (mean 29). Lymph node metastases were observed in 16 subjects aged 20-72 and distant metastases in 4 subjects aged 28-69. Forty-one subjects had pheochromocytoma detected at age 18-67 (mean 36). Amongst the 28 subjects with MTC and pheochromocytoma, six developed pheochromocytoma before MTC. Six subjects had HPT diagnosed at age 26-52 (mean 39). Eighteen subjects died; of the 16 with known causes of death, 8 died of pheochromocytoma and 4 of MTC. Penetrance for MTC is 52% by age 30 and 83% by age 50, for pheochromocytoma penetrance is 20% by age 30 and 67% by age 50, and for HPT penetrance is 3% by age 30 and 21% by age 50. These data provide, for the first time, RET C634W-specific neoplastic risk and age-related penetrance profiles. The data may facilitate risk assessment and genetic counseling

Version 3

Discussed at October 30, 2013 reference committee meeting and discussion continued via email.
Approved for publication

Review second yearly.

31/07/2015

Link to AGSA changed to Genetic Alliance Australia.

07/01/2016

Sentence added to Risk Management template: "The impact of lifestyle on cancer risk should be discussed".

14/04/2016

Sentence added to Risk Management template: "This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour. The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up".

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au